An unplanned interim analysis of the registry-based SWEDEPAD clinical trial, in which patients with peripheral arterial disease received treatment with paclitaxel-coated (drug-coated balloons or drug-eluting stents) or uncoated endovascular devices, “did not show a difference between the groups in the incidence of death” during one to four years of follow-up. This conclusion was published today by Mårten Falkenberg, Joakim Nordanstig (Gothenburg University, Gothenburg, Sweden) and colleagues in the New England Journal of Medicine (NEJM).
Falkenberg et al conducted the analysis against a backdrop of “concern about an increased risk of death associated with the use of paclitaxel-coated angioplasty balloons and stents in lower-limb endovascular interventions for symptomatic peripheral arterial disease”. They relay that data for the analysis was from the multicentre, randomised, open-label, registry-based SWEDEPAD (Swedish drug elution trial in peripheral arterial disease) clinical trial.
At the time of their analysis, the authors detail, 2,289 patients had been randomly assigned to treatment with either drug-coated devices (the drug-coated device group, 1,149 patients) or treatment with uncoated devices (the uncoated device group, 1,140). They state that paclitaxel was used as the coating agent for all the drug-coated devices.
Falkenberg et al detail that randomisation was stratified according to disease severity on the basis of whether patients had chronic limb-threatening ischaemia (1,480 patients) or intermittent claudication (809 patients), and that the single endpoint for this interim analysis was all-cause mortality.
Writing in NEJM, the authors communicate that no patients were lost in the mean 2.49-year follow-up period, during which 574 patients died, including 293 patients (25.5%) in the drug-coated device group and 281 patients (24.6%) in the uncoated device group (hazard ratio, 1.06; 95% confidence interval, 0.92–1.22).
At one year, Falkenberg and colleagues write that all-cause mortality was 10.2% (117 patients) in the drug-coated device group and 9.9% (113 patients) in the uncoated device group. During the entire follow-up period, they found that there was “no significant difference in the incidence of death between the treatment groups” among patients with chronic limb-threatening ischaemia (33.4% [249 patients] in the drug-coated device group and 33.1% [243 patients] in the uncoated device group) or among those with intermittent claudication (10.9% [44 patients] and 9.4% [38 patients], respectively).
In the discussion of their findings, the authors acknowledge that this interim analysis “was not a prespecified part of the trial protocol”. They respond to this limitation by noting a twofold rationale behind publishing these total mortality data ahead of completion of the trial: “First, we sought to reduce patients’ and physicians’ concerns regarding the safety of paclitaxel-coated devices, and second, we considered the data to be important to support completion of ongoing trials investigating the efficacy of such devices in peripheral arterial disease.” They add that this analysis was recommended by an independent data and safety monitoring committee “in order to alleviate patients’ and physicians’ concerns” surrounding paclitaxel safety.
Falkenberg and colleagues recognise a number of other limitations to their unplanned interim analysis, including the fact that the open-label design “could have the potential to introduce bias”. However, they point out that the endpoint of all-cause mortality used “is less sensitive to this particular limitation than more subjective outcomes”.
Another drawback the authors recognise relates to the fact that there were few deaths among patients with intermittent claudication, resulting in the confidence interval for that particular group of patients being wide (ranging from 0.72 to 1.93). As a result of this, the investigators write that they “cannot completely exclude the possibility of a difference in mortality in this subgroup”.
Falkenberg et al identify the use of ‘low-dose’ (rather than ‘high-dose’) paclitaxel-coated devices being “relatively common” in the trial as another limitation, which “may have influenced” their results.
In addition, they note that there was variation in the treatment effect among centres, although they write that it “seems likely that this variation is due to chance rather than to variation in centre characteristics”.
Finally, they highlight that no analysis of the efficacy of paclitaxel-coated devices is included in this interim report. They write: “These data are planned to be provided in the final clinical trial report after formal completion of the trial”.
At the end of their discussion, Falkenberg and colleagues stress that the SWEDEPAD trial “was not primarily intended for analysis of total mortality,” pointing out that the main purpose was “to determine whether drug-coating technology ultimately improves the lives of patients with symptomatic peripheral arterial disease by preventing amputation and improving health-related quality of life”.
Because this interim analysis “does not show a significantly higher incidence of death resulting from the use of paclitaxel-coated devices,” the authors conclude with their belief that “equipoise remains,” detailing that recruitment has been resumed with enrolment of patients in both the chronic limb-threatening ischaemia cohort and the intermittent claudication cohort.
The authors write that the trial is funded by grants from the Swedish Research Council, the Swedish Heart-Lung Foundation, and Region Västra Götaland. They also communicate that “all the companies that provide drug-coated balloons and drug-coated stents for patients in Sweden with peripheral arterial disease are supporting the trial by providing price discounts on their devices”.